Fosinopril sodium, [1[S*(R*)], 2.alpha.,4.beta.]-4-cyclohexyl-1-[[[2-methyl-1-(1-oxopropoxy)propoxy](4-ph enylbutyl)phosphinyl]acetyl]-L-proline, monosodium salt, having the structural formula ##STR3## is currently being evaluated as an antihypertensive agent.
Petrillo, Jr. in U.S. Pat. Nos. 4,337,201 and 4,384,123 discloses various phosphinylalkanoyl substituted prolines having angiotensin converting enzyme inhibition activity including fosinopril.
Petrillo, Jr. et al. in U.S. Pat. No. 4,873,356 discloses a process for preparing fosinopril in which a phosphinic acid ester of the formula ##STR4## wherein R.sub.3 is benzyl or substituted benzyl, n is zero or one, and R.sub.1 is lower alkyl, aryl, arylalkyl, cycloalkyl or cycloalkylalkyl is reacted with a halo ester of the formula ##STR5## wherein Hal is Cl or Br, X is hydrogen, lower alkyl, or phenyl, and Y is hydrogen, lower alkyl, phenyl, or alkoxy to form the phosphinic acid diester of the formula ##STR6## It is disclosed that this reaction is carried out in the presence of an organic base such as triethylamine, which is preferred, pyridine, tripropylamine, diazabicycloundecene or any other common organic bases and an organic solvent such as toluene, which is preferred, acetonitrile, dichloromethane, ethyl ether, tetrahydrofuran, or dioxane and optimally in the presence of a catalyst such as tetrabutylammonium sulfate and sodium iodide.
The resulting phosphinic acid diester is then hydrogenated to form a pair of racemic mixtures which are separated by fractional crystallization to give a single racemic mixture. This racemic mixture is treated with a resolving agent such as L-cinchonidine or other optically active amine to separate out the desired intermediate. ##STR7## This intermediate wherein R.sub.1 is phenylbutyl, n is zero, R.sub.2 is hydrogen, Y is ethyl, and X is isopropyl is then coupled to 4-trans-cyclohexyl-L-proline, hydrochloride salt in the presence of a coupling agent to give fosinopril.